Therapeutic salts of vanillic acid esters



Patented Apr. 13, 1954 THERAPEUTIC SALTS F VANILLIGACID ESTERS.

IrwinA'. Pearl,Appleton, Wis., assignor to The "Institute of P'aperChemistry, Appleton, 'Wis.,

a corporation 'of Wisconsin No .Drawing. Application March 8,1952,Serial No. 275,690

' Claims;

In general, "the present invention relates to products which areeffective against histoplasma capsulatum and coccidioi des immitis and,more particularly,'the invention relates to water soluble salts of alky1vanillates which are therapeutically effective against disseminatedhistoplasmosis and coccidioidomycosis.

In recent years,investigations have shown that the lower-alkyl (lessthan eight carbon atoms) vanillates are effective against histoplasmacapsulatum and coccidioides immitis so that certain infections such asdisseminated histo-plasmosis and coccidioidomycosis may be effectivelytreated through the use of ethyl vanillate and other lower alkylvanillates. Indeed, several-"case histories have dramm'aticallyillustrated the general effectiveness of these lower alkyl vanillatesagainst disseminated histop-lasmosis.

However, since the lower alkyl vanillates .are

not water-soluble, it has been'necessary to dissolve the alkylvanillatesin olive oil, a 40 per cent solution usually being'prepared, in order toadminister the lower alkylvanillates to human beings. The oliveoil-vaniliate solution then. has been given orally. Suchadministrationof the vanillates has been necessary because, as pointed has'been arelatively smallmargin between therapeutically effective doses of theloweralkyl vanillates and the doseswhich are toxic. "The problem,therefore, has-been to .broaden. the margin. so as to make possibleestablishment of higher levels of thea'lkyl'vanillatesin the humansystem while at the same time keeping the amounts ofvanillatesadministered to human beings below toxic levels.

Accordingly, an object of the present invention is to provide newcompounds which may be injected into the human system in a manner suchthat increased amounts of the alkyl vanillates may be introduced intothe human system without causing toxicity. As will appear hereinafter,this and other objects of the invention are accomplished by theformation of an alkali metal salt of the lower alkyl (less than eightcarbon atoms) vanillates which is water soluble and which will 2 breakup in the human system so as'to free the alkyl vanillates from thealkali metal 'so that it may be therapeutically effective'againsthistoplasmosis and coccidioidomycosis. As used herein, the term alkalimetal shall consist of sodium, potassium, lithium and ammonium.

'In preparing the salts of the invention, an alkali 'metal loweralk'ylate (one to four carbon atoms) is usuallyjpreparecl and thealkylate is then combined with a lower alkyl vanillate, causing aprecipitate to :be formed. However, the am.- monium salt is usually madeby'introducing ammonia gas into a lower alkyl vanillatesolution,

thereby producing a precipitate. The precipitate comprises an alkalimetal salt of the alkyl vanillate. The mixture is .filtered and theprecipitate washed with an alcohol andthen with ether. After washing,the precipitate is dried and may then be dissolved .in distilled waterand used against histoplasma capsulatum and coccidioides immitis.

The salts of potassium and lithium are not generally satisfactory fortherapeutic use in human beings and therefore, for such therapeuticpurposeathe lower alkylvanillate salts of sodium and ammonium arepreferred. The alkali metal salts are solubleinwater, as indicated, butthe alkali metal separates from the alkyl vanillate when neutralized.Accordingly, when an alkali metal .salt of a lower alkyl vanillate isintroduced intramusculaizly, intravenously, or subcutaneously into humanbeings, the lower valkyl vanillate separates .fromthe alkali metal andis in a free form to act against histo plasma-capsulatum andcoccidioides .immitis.

Ithas been found that of the lower alkyl vanil- 1 lates, .iso-butylvanillate. is particularly effective um saltsof these alk'yl vanillates.are preferably made for. .use treating human beings.

As a specific example of the preparation of the salt of the invention, asolution of sodium ethylate was first prepared by placing 42.7 grams ofmetallic sodium. in 2500 cc. of absolute ethanol under refluxconditions. After reflux, the solution was cooled and was then mixedwith a cold solution (15 C.) of iso-butyl vanillate which had beendissolved in 1250 cc. of absolute ethanol. Mixing of the two solutionswas accomplished by stirring and, after a few minutes of stirring, themixture became thick with fine white needles of the sodium salt ofiso-butyl vanillate. The cooled mixture was filtered and the precipitatewashed with cold anhydrous ethanol and then with large volumes ofabsolute ether. After washing with the ether, the sodium salt ofisobutyl vanillate was dried. The salt was relatively stable and wasvery soluble in water, the salt giving a clearsolution having a pHbetween and 11. It was found that the iso-butyl vanillate precipitatedfrom an aqueous solution by the addition of acid to the point where thesolution was substantially neutral. I

As another example of the preparation of a salt of the invention, asolution comprising 340 grams of iso-butyl vanillateand 1500 cc. ofabsolute ether was prepared. The solution was prepared. in a flask anddry ammonia gas was bubbled into the flask until it became almost solidwith a white granular precipitate. The precipitate was filtered andthoroughly washed with cold C.) anhydrous ether and then air dried. Inthis manner; 89 grams of the am- .monium salt of iso-butyl vanillate wasprepared,

the salt having a slight ammoniacal odor and being soluble in water. Theaqueous solution had a pl-I-of about 9.

trate again treated with the ammonia gas.

Finally, 364 grams of pure ammonium salt of isobutyl vanillate wasobtained.

The ammonium salt is somewhat more satisfactory for use in the treatmentof human beings because of its lower pH and, consequently, loweralkalinity. Y

The ammonium salt of ethyl vanillate was prepared by preparing asolution ofBOO grams. of ethyl vanillate in 1500 cc. of absolute ether.This solution was then treated with dry ammonia gas and the precipitaterecovered as inv the previous example.

' The ammonium salt of n-propyl vanillate was made by first preparing acold solution of 300 grams of n-propyl vanillate in 1500 cc. of absoluteether. This solution was also treated with dry ammonia gas until theflask containing the solution became solid with the ammonium salt ofn-propyl vanillate. The salt was filtered and washed with absolute etherand air dried. The filtrate was again treated with ammonia gas torecover additional amounts of ammonium salt n-propyl vanillate. V

The lithium and potassium salts of the lower alkyl vanillates may beprepared by first preparing a solution of potassium or lithium ethylate,this being accomplished by placing 1.9 moles and combined with a coldsolution comprising about two moles of a lower alkyl vanillate and 1250cc. of absolute ethanol. When these solutions are combined, thepotassium or lithium salt will precipitate and may be recovered byfiltering. A more pure salt may be had by washing the filtered salt withether and air drying the product.

In the foregoing, I have disclosed certain products which have unusualvalue in the treatment of disseminated histoplasmosis andcoccidioidomycosis. These products may be easily administered to humanbeings and higher efiective therapeutic levels may be achieved in thehuman body without danger of toxicity.

The various products which are believed to be new are set forth in thefollowing claims.

I claim:

1. An alkali metal salt of a lower alkyl vanillate, said salt being incrystalline form and being soluble in water in amounts suflicient toprovide a therapeutically active composition.

2. The sodium salt of a lower alkyl vanillate, said salt being incrystalline formandbeing soluble in water in amounts suflicient toprovide a therapeutically active composition.

3. The ammonium salt of a lower alkyl vanillate, said salt being incrystalline form and being soluble in water in amounts sufficient toprovide a therapeutically active composition.

4. An alkali metal salt of ethyl vanillate, said salt being incrystalline form and being soluble in water in amounts sufficient toprovide a therapeutically active composition.

5. An alkali metal salt-of iso-butyl vanillate, said salt being incrystalline form and being soluble in water in amounts sufficient toprovide a therapeutically active composition.

6. An alkali metal salt of n-propyl vanillate, said salt being incrystalline form and being soluble in water in amounts sufficient toprovide a therapeutically active composition.

7. A therapeutic compound comprising the'sodium salt of iso-butylvanillate, said salt being in crystalline form and being soluble inwater in amounts suflicient to provide a therapeutically activecomposition. a

8. A therapeutic compound comprising the ammonium salt of iso-butylvanillate, said salt being in crystalline form and being soluble inwater in amounts suflicient to provide a therapeutically activecomposition.

9. A therapeutic compound comprising the sodium salt of n-propylvanillate, said salt being in crystalline form and being soluble inwater in amounts sufiicient to provide a therapeutically activecomposition, a

10. A therapeutic compound comprising the ammonium saltof n-propylvanillate, said salt being in crystalline form and being soluble inwater in amounts sumcient to provide a therapeutically activecomposition.

References Cited in the file of this patent .Tiemann et al., Ber. Deut.Chem., 10, 59-60 (1877).

1. AN ALKALI METAL SALT OF A LOWER ALKYL VANILLATE, SAID SALT BEING INCRYSTALLINE FORM AND BEING SOLUBLE IN WATER IN AMOUNTS SUFFICIENT TOPROVIDE A THERAPEUTICALLY ACTIVE COMPOSITION.